Project Summary/Abstract Natural products and derivatives are a significant potential source of new drug candidates due to their high complexity and biological activity. However, chemical synthesis is often too time and resource-intensive to enable timely development of natural product derivatives as drugs. In contrast, nature has an incredible proficiency for the synthesis of complex chemical structures. Many organisms have evolved powerful enzymes that have been used by chemists to produce natural products cost-effectively and in large quantities via fermentation. However, it remains a significant challenge to modify the structure of natural products to improve pharmacokinetic properties and increase efficacy. This proposal seeks to develop multifunctional catalysts that mimic the synthetic efficiency of enzymes and benefit from the versatility of chemical synthesis. To accomplish this, we will use structurally well-defined helical peptides to scaffold multiple catalysts (e.g. organocatalysts, transition metals, Lewis acids) in close proximity to enable enzyme-like catalysis. Preliminary data from our laboratory confirm that helical peptides can preorganize multiple catalysts in such a way to facilitate proximity- accelerated reactivity and selectivity based on the binding of multiple substrates. In this proposal, we will first optimize the efficiency of our enzyme-like catalysts to maximize the enhanced reactivity and selectivity already observed to levels that approach the efficiency of natural enzymes. These efforts will be guided by predictive computational models developed in our group. We will then capitalize on these proximity effects to rationally design multifunctional catalysts and multi-catalyst systems that achieve unprecedented reactivity and enable bond constructions that cannot be performed with traditional catalysts. We will also develop multifunctional catalysts that overcome inherent reaction selectivity by preorganizing reacting partners to achieve novel selectivity (regioselectivity, enantioselectivity). These efforts will enable new reactions that streamline the synthetic process, improve access to complex molecules for drug discovery, and enable cost-effective development of new medicines. The use of helix-templated catalysts will enable new synthetic strategies based on the ability of the catalysts to bind and activate intermediates in close proximity, leading to lower step counts in synthesis. By doing so, this project has the potential to greatly affect overall human health by advancing drug discovery and enabling cost-effective production of new pharmaceuticals. The interdisciplinary research proposed herein will enable significant innovation in synthetic chemistry, de novo enzyme design, and drug discovery, and when successful, will have a broad impact in the areas of catalysis, synthetic design, and medicine.